Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation

Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca2+ leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1–calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Basil of Caesarea

Basil of Caesarea is thought of most often as an opponent of heresy and a pioneer of monastic life in the eastern church. In this new biographical study, however, controversy is no longer seen as the central preoccupation of his life nor are his ascetic initiatives viewed as separable from his pastoral concern for all Christians. Basil's letters, sermons, and theological treatises, together with the testimonies of his relatives and friends, reveal a man beset by doubt. He demanded loyalty, but gave it also, and made it a central feature of his church. In Rousseau's portrait, Basil's understanding of human nature emerges as his major legacy

Sheet-like emplacement of satellite laccoliths, sills, and bysmaliths of the Henry Mountains, Southern Utah

International audienceSmall intrusions (<3 km 2) on the margins of the Henry Mountains intrusive complex of southern Utah are exceptionally well exposed in three dimensions and have a variety of shapes. Our examination of the geometry, structures, and fabric of the Maiden Creek sill, Trachyte Mesa laccolith, and the Black Mesa bysmalith (cylindrical intrusion bounded by vertical faults) suggests that this range of intrusion geometry may refl ect a continuum of igneous emplacement as volume increases through magma sheeting. Intrusions begin as thin sills and through incremental injection of additional sheets, infl ate into laccoliths. Marginal wall rocks are strained and rotated upward. Further sheet emplacement leads to the formation of a fault at the margin of the infl ating intrusion. This fault accommodates piston-like uplift of the intrusion's roof and results in the formation of a bysmalith. All three of these intrusions exhibit evidence for sheeting, although the evidence is weakest on the margins of the Black Mesa bysmalith. Solid-state shear zones exist between sheets in the Maiden Creek sill and on the margins of the Trachyte Mesa laccolith. Cataclastic zones also separate sheets within the Trachyte Mesa laccolith. Evidence for sheeting in the interior of the Trachyte Mesa laccolith is solely based on differences in weathering and jointing patterns. Evidence for sheeting on the margins of the Black Mesa bysmalith is based on the differences in lineation patterns and also on the distribution of cataclastic zones

Emplacement of multiple magma sheets and wall rock deformation: Trachyte Mesa intrusion, Henry Mountains, Utah

International audienceA detailed structural and rock magnetic study of the Trachyte Mesa intrusion and deformed sedimentary wall rocks, Henry Mountains, Utah, indicates that the intrusion grew vertically and horizontally by the accumulation of multiple horizontal magma sheets. 2–3 cm thick shear zones recognized by intensely cataclasized plagioclase phenocrysts define the contact between sheets. Sheets have bulbous and / or steep frontal terminations and are flat on top. The foliation within the interior of the sheets, near the frontal termination, is subvertical. This steep foliation rotates into the subhorizontal shear zones near the top and bottom contacts and provides a magma flow direction indicator. Away from the frontal termination, the interior foliation rotates to become subhorizontal, similar to the fabric in recent analog experimental studies. Sheets are interpreted as being emplaced as plug flows. Both the field fabric and the rock magnetic data collected from 103 locations on the top of the intrusion and from 73 locations along a vertical cross section exposed in a stream gorge support a multi-stage model of intrusion growth. Emplacement begins as narrow magma channels and magma spreads radially outward from the channels to form sheets. Sheets are stacked upon one another and stop at the same lateral termination. The deformation of the sandstones at the margin of the intrusion, which are rotated upward from the margin to become the roof, is partitioned into layer parallel extension, shearing and layer-parallel shortening components. Bulk strain within the thickest sandstone layer indicates not, vert, similar20% thinning and microstructures indicate that the thinning was accommodated by grain-scale fracture-induced porosity collapse. Extension occurred as the layer was stretched over the margin of the rising intrusion. Shearing and layer-parallel shortening are a result of coupling with the underlying sheets as they advanced and accommodated through numerous faults parallel to bedding and at low angles to bedding. The deformation of thinner sedimentary layers is consistent with the sedimentary layering immediately in front of an advancing sheet being translated upward and over the top of the sheet as the hinge zone migrates with the front edge of the advancing sheet

Climate or migration: what limited European beech post-glacial colonization?

International audienceAimDespite the recent improvements made in species distribution models (SDMs), assessing species' ability to migrate fast enough to track their climate optimum remains a challenge. This study achieves this goal and demonstrates the reliability of a process‐based SDM to provide accurate projections by simulating the post‐glacial colonization of European beech.LocationEurope.MethodsWe simulated the post‐glacial colonization of European beech over the last 12,000 years by coupling a process‐based SDM (PHENOFIT) and a new migration model based on Gibbs point processes, both parameterized with modern ecological data. Simulations were compared with palaeoarchives and phylogeographic data on European beech.ResultsModel predictions are consistent with palaeoarchives and phylogeographic data over the Holocene. The results suggest that post‐glacial expansion of European beech was limited by climate on its north‐eastern leading edge, while limited by its migration abilities on its north‐western leading edge. The results show a mean migration rate of beech varying from 270 m yr −1 to 280 m yr−1 and a maximum migration rate varying from 560 m yr−1 to 630 m yr−1, when limited and not limited by climate, respectively. They also highlight the relative contribution of known and suspected glacial refugia in present beech distribution and confirm the results of phylogeographic studies.Main conclusionsFor the first time, we were able to reproduce accurately the colonization dynamics of European beech during the last 12 kyr using a process‐based SDM and a migration model, both parameterized with modern ecological data. Our methodology has allowed us to identify the different factors that affected European beech migration during its post‐glaciation expansion in different parts of its range. This method shows great potential to help palaeobotanists and phylogeographers locate putative glacial refugia, and to provide accurate projections of beech distribution change in the future

Mechanisms and duration of non-tectonically assisted magma emplacement in the upper crust: The Black Mesa pluton, Henry Mountains, Utah

International audienceA new study of Black Mesa pluton (Henry Mountains, Colorado Plateau, Utah, USA) indicates that it is a classic example of a small upper-crustal pluton assembled over a few years by incremental amalgamation of discrete magma pulses. The results of our petrostructural study of the pluton interior allow us to constrain the geometry, kinematics and timing of the processes. The symmetric internal fabric is interpreted as an evidence for a feeding by below and not laterally. The observed rotation of the lineation, from WNW–ESE on the very top to NNE–SSW below, lead us to propose that the fabric at the base of the pluton is a record of magma infilling process, and the fabric at the very top is a record of the strain due to the relative movement between magma and wallrocks. A consequence is that except at the contact between pluton and wallrocks (top and margins), the stretching direction, recorded by the lineation, is not parallel to the flow direction of the magma i.e. displacement. The Black Mesa pluton is a sheeted laccolith on its western edge and a bysmalith on its eastern edge. This E–W asymmetry in pluton geometry/construction and the symmetrical internal fabric indicates that the apparently different west and east growth histories could have occurred simultaneously. Our field data indicate pluton growth through an asymmetric vertical stacking of sill-like horizontal magma sheets. One-dimensional thermal models of the pluton provide maximum limits on the duration of its growth. We have constrained the number, the thickness, and the frequency of magma pulses with our structural observations, including: (1) the emplacement of the pluton by under-accretion of successive magma pulses, (2) the absence of solid-state deformation textures at internal contacts, and (3) the apparent absence of significant recrystallization in the wallrocks. Our results suggest that the emplacement of the Black Mesa pluton was an extremely rapid event, with a maximum duration on the order of 100 years, which requires a minimum vertical displacement rate of the wallrocks immediately above the pluton greater than 2 m/yr. Finally, our data show that the rates of plutonic and volcanic processes could be similar, a significant result for interpretation of magma transfer in arc systems